Male impotence is a widespread syndrome affecting at least 10-15% of the human male population. It is estimated that in the United States alone, over ten million men suffer from varying degrees of impotence.
In principle, any man over the age of forty years may experience impotence occasionally due to neuroendocrine failures associated with ageing.
Impotence, which may bring suffering to the life of the afflicted individuals and those surrounding them, may be caused by both psychological or physiological problems. An additional problem associated with impotence is that often a suffering individual hesitates to seek medical help, especially in view of the limited convenient remedies available to the physician. Modes of treatment of impotence caused by organic reasons may involve surgery and implantation, as well as injection of smooth muscle relaxants such as papaverine or phenoxybenzamine.
Treatment of impotence with penile implants entails very serious disadvantages. The treatment requires surgery and results in a total and irreversible destruction of the erectile tissues of the penis precluding the ability of normal erection in the future.
Treatment of impotence with papaverine or phenoxybenzamine often results in priapism, a locking-up of an erection for a long period of time, typically a few hours and up to a period of twenty four hours. Apart from the embarrassment that priapism may cause, it is usually painful and may irreversibly damage erectile tissues. To be relieved, it may require in some cases pharmacological intervention. Even when priapism does not occur with the use of papaverine, such use is associated with a painful burning sensation in the first two minutes after injection, and there arc indications that repeated use of papaverine causes extensive intracavernous fibrosis. In addition, phenoxybenzamine is suspected to be carcinogenic and therefore cannot be considered as a future effective drug for impotence
In view of all the above, there is a need for a discreet, efficient and self-controlled treatment of impotence. The transdermal application of drugs seems to offer an attractive approach for such treatment, in view of the fact that such treatment is self-controlled and discreet and does not require any surgical intervention. The treatment using the drugs and pharmaceutical compositions according to the invention does not involve priapism.
The mechanism of penile erection requires the intactness of the endocrine system, the nervous systems and the vascular system. Vasoactive intestinal peptide (VIP) which was first isolated by S. Said and V. Mutt.sup.(1) and exhibits a wide range of physiological activities, was recently found to fulfil several criteria of a neurotransmitter mediating penile erection.sup.(2). VIP was detected in fibres innervating cavernous smooth muscle. It was also elevated during erection.sup.(3,4) and decreased in impotent men.sup.(5). Additionally, injection of exogenous VIP induced penile erection in man.sup.(3). It was recently shown that systemic injection of VIP can stimulate sexual behaviour in rats with experimentally reduced masculine potential.sup.(6) and that lipophilic derivatives of VIP, and of the VIP.sup.7-28 and VIP.sup.16-28 fragments may be applied transdermally to enhance sexual behaviour.sup.(7). In a study on normal subjects it was shown that injection of up to 20.mu.g of VIP into the corpus cavernosum of a normal male, without subjecting the male to sexual stimulus, caused only slight swelling of the penis but not erection. However, when coupled with sexual stimulation, injection into the corpus cavernosum of as little as 1 .mu.g of VIP facilitated full erection.sup.(8).
There are also known.sup.(9) VIP analogs in which some of the amino acids of the natural VIP sequence are replaced by others and in which the histidine in position 1, the so-called N-terminus, may optionally be acetylated. No enhancement of the sexual behaviour of males by such compounds was reported.
Dimaline et al..sup.(10) disclose a VIP derivative wherein X.sup.2 is Leu or Thr as an alternative amino acid to Met in the 17th position. However, they failed to suggest a modified molecule containing both an amino acid replacement and a covalently attached lipophilic, e.g. stearoyl residue. Moreover, such modification could result in an inactive analog due to enhancement of intramolecular hydrophobic interactions.
Japanese Kokai No, 4-59794 published on Feb. 26, 1992 describes an amidated homoserine derivative of modified VIP represented by L-leucine-17-VIP-HSe-NH.sub.2 indicated for treatment of impotence and prevention of bronchial contraction by injection administration.
It is the object of the present invention to provide improved agents and compositions for the transdermal treatment of male impotence.